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Merck KGaA, Darmstadt, Germany, Assigns Chimeric Antigen Receptor T-cell (CAR-T) Rights to Intrexon

On December 20, 2018 Merck KGaA, Darmstadt, Germany, a leading science and technology company, reported that through its wholly owned subsidiary, Ares Trading, it has evolved its agreement with Intrexon Corporation (NASDAQ: XON) for the development of Chimeric Antigen Receptor T-cell (CAR-T) therapies, genetically engineered T-cells with synthetic receptors that recognize a specific antigen expressed on tumor cells (Press release, Merck KGaA, DEC 20, 2018, View Source;utm_medium=email&utm_campaign=press-mailer&utm_content=en&global_redirect=1 [SID1234532177]). The agreement with Intrexon and its wholly-owned subsidiary, Precigen, Inc. enables Merck KGaA, Darmstadt, Germany, to continue to implement its focused R&D strategy, while maintaining an investment in the future potential of next-generation CAR-T development.

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Under the terms of the agreement, Merck KGaA, Darmstadt, Germany, will assign its exclusive CAR-T development rights to Intrexon. Merck KGaA, Darmstadt, Germany will receive shares of Intrexon common stock valued at $150 million in exchange for assigning Intrexon its CAR-T rights.

"Merck KGaA, Darmstadt, Germany, is excited to maintain its interest in the potential of CAR-T technology, which may offer significant future benefits to patients fighting cancer," said Belén Garijo, Member of the Executive Board and CEO Healthcare, Merck KGaA, Darmstadt, Germany. "The agreement is also illustrative of our efforts to enhance our focus on accelerating the delivery of our innovative clinical pipeline to patients."

Merck KGaA, Darmstadt, Germany, first entered into a collaboration and license agreement with Intrexon in 2015 to develop and commercialize CAR-T cancer therapies utilizing Intrexon’s proprietary RheoSwitch Therapeutic System and the Sleeping Beauty non-viral gene integration technology. The combination of these platforms enables regulation of gene expression and delivery with a non-viral approach and preclinical data indicate the potential to improve therapeutic safety and facilitate shortened manufacturing to improve time-to-treatment. As of December 31, 2017, these rights were considered intangible assets not yet available for use with a carrying amount of € 104 million.

"Merck KGaA, Darmstadt, Germany’s leading immuno-oncology research and commitment to developing innovative medicines made them an ideal partner for us in advancing targeted and controllable CAR-T therapies," said Helen Sabzevari, PhD, President of Precigen. "We look forward to continued development of these promising treatments with the goal of delivering more cost-effective, powerful, and precise therapies to patients in need."

In addition to receiving $150 million of Intrexon common stock, this agreement also includes a further $25 million investment in Intrexon. In return, Merck KGaA, Darmstadt, Germany, will receive a $25 million convertible note, providing the option to receive either Precigen or Intrexon stock. The closing of the transactions contemplated by the agreement is subject to customary closing conditions, including the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act.

Mustang Bio Receives Orphan Drug Designation for MB-102 (CD123 CAR T) for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm

On December 20, 2018 Mustang Bio, Inc. ("Mustang") (NASDAQ: MBIO), a company focused on the
development of novel immunotherapies based on proprietary chimeric antigen receptor engineered T cell (CAR T)
technology and gene therapies for rare diseases, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to MB-102 (CD123 CAR T) for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and incurable blood cancer with a median survival of less than 18 months and no standard of care (Press release, Mustang Bio, DEC 20, 2018, View Source [SID1234532176]).

Martina Sersch, M.D., Ph.D., Chief Medical Officer of Mustang, said, "We are pleased to receive Orphan Drug
Designation for MB-102, which has shown the potential to address an area of high unmet medical need. This significant milestone for Mustang will provide additional market exclusivity and financial benefits to advance MB-102, which we believe is an important new treatment for patients with BPDCN. Based on the Phase 1 data presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2017 and the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference on Tumor Immunology and Immunotherapy in November 2018, we expect to initiate a multicenter Phase 1/2 clinical trial in patients with acute myeloid leukemia (AML), BPDCN and high-risk myelodysplastic syndrome in 2019."

MB-102 is currently being studied in a single center, first-in-human Phase 1 dose-escalation clinical trial evaluating the
safety and anti-tumor activity of escalating doses of MB-102 in patients with relapsed or refractory AML (cohort 1) and BPDCN (cohort 2). Patients receive a single dose of MB-102 with an option for a second infusion if they continue to meet safety and eligibility criteria and still have CD123+ disease. MB-102 has demonstrated complete responses at low doses in AML and BPDCN without dose-limiting toxicities.

The FDA grants Orphan Drug Designation to drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides certain incentives, such as tax credits toward the cost of clinical trials and prescription drug user fee waivers. If a product holding Orphan Drug Designation receives the first FDA approval for the disease in which it has such designation, the product is entitled to seven years of market exclusivity, which is independent from intellectual property protection.

About Blastic Plasmacytoid Dendritic Cell Neoplasm
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and incurable blood cancer with a median survival of less
than 18 months and no standard of care. High levels of CD123 expression is one of the diagnostic hallmarks of BPDCN, making CD123 an attractive target for T cell-based adoptive immunotherapy.

About MB-102 (CD123 CAR T)
MB-102 (CD123 CAR T) is a CAR T cell therapy that is produced by engineering patient T cells to recognize and eliminate CD123-expressing tumors. CD123 is widely expressed on bone marrow cells of patients with myelodysplastic syndromes, as well as in hematologic malignancies including AML, B-cell acute lymphoblastic leukemia, hairy cell leukemia, BPDCN, chronic myeloid leukemia and Hodgkin’s lymphoma.

In the first-in-human clinical trial at City of Hope (NCT02159495), MB-102 has demonstrated complete responses at low doses in AML and BPDCN without dose-limiting toxicities, as reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2017 and the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference on Tumor Immunology and Immunotherapy in November 2018. Dose escalation continues at City of Hope in both indications.

Ziopharm Oncology and TriArm Therapeutics Establish Joint Venture to Develop and Commercialize Sleeping Beauty CAR T in China, Taiwan and Korea

On December 19, 2018 Ziopharm Oncology, Inc. (Nasdaq:ZIOP) and TriArm Therapeutics, Ltd, reported they will launch Eden BioCell, Ltd. to lead clinical development and commercialization of Sleeping Beauty-generated CAR-T therapies in the People’s Republic of China (including Macau and Hong Kong), Taiwan and Korea (Press release, Ziopharm, DEC 19, 2018, View Source [SID1234573334]). TriArm is a cell therapy company with operations in Germany, China and the United States that was formed by Panacea Venture Healthcare, a fund co-founded and managed by James Huang, Managing Partner of Kleiner Perkins Caufield & Byers China (KPCB China).

For the territory of China, Taiwan and Korea, Ziopharm will license the rights to Eden BioCell for third-generation Sleeping Beauty-generated CAR-T therapies targeting the CD19 antigen. Eden BioCell will be owned 50-50 by Ziopharm and TriArm. TriArm has committed up to $35 million to this joint venture. Under the terms of the agreement, Eden BioCell has rights in the region to CAR-T cells very rapidly manufactured in two days or less using the Sleeping Beauty platform to express a CD19-specific CAR and membrane-bound interleukin-15, or mbIL15, along with a kill switch. Ziopharm CEO Laurence Cooper, M.D., Ph.D., and Panacea Venture Healthcare Managing Director James Huang will serve on Eden BioCell’s Board of Directors and each party will share decision-making authority.

"Since 2017, we have been doing diligence on ways to address the many obstacles that exist in the production and commercialization of CAR-T immunotherapy. Viral-based CAR-T therapies already are facing cost constraints and limited commercial success in U.S. and EU markets due to the expense and complexity in manufacturing, and this problem will be exacerbated in China, with its healthcare system, reimbursement structure and large patient population," said Mr. Huang. "I am excited to be working with Ziopharm’s Sleeping Beauty platform, which, as the most clinically-advanced non-viral approach to genetical modification of T cells, offers the best chance to simplify manufacturing, reduce costs, and most importantly, help the many patients who need access to these T-cell therapies."

"Advancing our Sleeping Beauty platform in the China region is a key part of both our business development and clinical development strategies," said Dr. Cooper. "James Huang has an outstanding track record of creating value in China, and he and the team at TriArm are ideal partners because they have entrenched relationships with front-line physicians and officials at leading hospitals and regulatory bodies, a commitment to conduct high-quality trials, and state-of-the-art facilities with good manufacturing practices."

TriArm will manage all clinical development to execute trials in China for Eden BioCell. The TriArm team has considerable experience in all areas of drug development, including scientific research, clinical and regulatory areas, as well as significant laboratory and manufacturing know-how regarding T-cell therapies.

Griffin Securities, Inc. acted as the financial advisor for Ziopharm for this licensing agreement.

Conference Call
Ziopharm will host a webcast and conference call on Wednesday, Dec. 19, at 8 a.m. ET to discuss this new joint venture. The call can be accessed by dialing 1-844-309-0618 (U.S. and Canada) or 1-661-378-9465 (international). The passcode for the conference call is 3272014. To access live webcast or the subsequent archived recording, visit the "Investors Events and Presentations" section of the Ziopharm website at www.ziopharm.com. The webcast will be recorded and available for replay on the Company’s website for two weeks.

Termination of a Material Definitive Agreement.

On December 19, 2018 On December 19, 2018, BeiGene, Ltd. (the "Company") reported that it received notice from Merck KGaA ("Merck KGaA") that Merck KGaA was terminating for convenience the parties’ License Agreement dated December 10, 2013, as amended, for the Company’s investigational RAF dimer inhibitor lifirafenib (BGB-283) in the People’s Republic of China ("PRC") (Filing, 8-K, BeiGene, DEC 19, 2018, View Source [SID1234532301]). As a result of such termination, Merck KGaA’s exclusive right of first negotiation to acquire exclusive commercialization rights under the lifirafenib RAF dimer program in the PRC was terminated and the Company is no longer required to pay Merck KGaA royalties on sales of lifirafenib in the PRC or entitled to receive future milestone payments from Merck KGaA for lifirafenib. The Company’s ex-PRC agreement with Merck KGaA on lifirafenib was terminated in March 2017.

Daiichi Sankyo Initiates First Novel-Novel Combination Study of Two Investigational Agents within its AML Franchise in Patients with AML

On December 19, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the first patient has been dosed in the first novel-novel combination study evaluating two investigational agents within its AML Franchise (Press release, Daiichi Sankyo, DEC 19, 2018, View Source [SID1234532207]). The phase 1 study will evaluate the safety and activity of the combination of a FLT3 inhibitor, quizartinib, and an MDM2 inhibitor, milademetan (DS-3032), in patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML) or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy, a very aggressive form of the disease associated with poor prognosis.

"We have initiated this combination study of quizartinib and milademetan in order to determine the safety and tolerability of the combination and if the addition of the MDM2 inhibitor milademetan may potentially further improve the outcomes of patients with relapsed/refractory FLT3-ITD AML beyond what has been previously reported with single agent quizartinib," said Arnaud Lesegretain, Vice President, Oncology R&D and Head, AML Franchise, Daiichi Sankyo. "In this study, we also are exploring the potential of the combination of quizartinib and milademetan in patients with newly-diagnosed FLT3-ITD AML who are unfit for intensive chemotherapy. This study is the first of several planned studies that will evaluate the potential of novel combinations within our investigational AML Franchise, as we are committed to continuously improving the standard of care for patients with AML."

Quizartinib is the first FLT3 inhibitor to demonstrate a survival benefit as an oral, single agent compared to chemotherapy in a randomized, phase 3 study (QuANTUM-R) in patients with FLT3-ITD AML, which was refractory or relapsed within six months of first remission, and single agent milademetan has demonstrated preliminary clinical activity in AML and myelodysplastic syndrome (MDS) in a phase 1 study.1,2 Additionally, preclinical research has shown that the combination of quizartinib and milademetan has greater activity in FLT3-ITD AML cells compared to the respective single agent treatments.3

In the QuANTUM-R study, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (>30 percent, any Grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia and vomiting, and the most common Grade ≥ 3 adverse drug reactions (>20 percent) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50 percent) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count and decreased platelet count. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

In addition to the quizartinib and milademetan combination study, an ongoing phase 1 study of milademetan has been expanded to include evaluation of milademetan in combination with the hypomethylating agent 5-azacitidine, an inhibitor of DNA methylation, in patients with newly-diagnosed AML unfit for intensive chemotherapy, relapsed/refractory AML or high-risk MDS.

About the Quizartinib/Milademetan Combination Study

The multi-center, non-randomized, phase 1, open-label, two-part study is investigating the safety and efficacy of the combination of quizartinib and milademetan in patients with relapsed/refractory FLT3-ITD AML or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy. The first part of the study (dose escalation) will assess the safety and tolerability of the combination to determine the dosing schedule, maximum tolerated dose and recommended dose for expansion. The second part of the study (dose expansion) will confirm the safety and tolerability at the recommended dose for expansion of the combination and will identify a recommended phase 2 dose. The primary objective of the study is safety. Secondary objectives include evaluation of pharmacokinetics and preliminary efficacy. The study is expected to enroll approximately 110 patients in the U.S., EU and Japan. For more information about the study, visit ClinicalTrials.gov.

About the Milademetan/5-Azacitidine Combination Study

The multi-center, non-randomized, phase 1, open-label, two-part study is investigating the safety and efficacy of milademetan as a single agent and in combination with the hypomethylating agent 5-azacitidine. The first part of the study (dose escalation) will evaluate the safety and tolerability and identify the maximum tolerated dose and recommended dose for expansion of milademetan as a single agent and in combination with 5-azacitidine in patients with relapsed/refractory AML or high-risk MDS. The second part of the study (dose expansion) will confirm the safety and tolerability at the recommended dose of milademetan in combination with 5-azacitidine and will identify a recommended phase 2 dose in patients with relapsed/refractory AML, newly-diagnosed AML unfit for intensive chemotherapy or high-risk MDS. The primary objectives of the study are safety and tolerability, maximum tolerated dose, recommended dose for expansion and response to treatment. Key secondary objectives include evaluation of pharmacokinetics and pharmacodynamic effects. The study is expected to enroll up to 200 patients in the U.S. For more information about the study, visit ClinicalTrials.gov.

About Acute Myeloid Leukemia and Myelodysplastic Syndrome

AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.4 In the U.S. this year, it is estimated that there will be more than 19,000 new diagnoses of AML and more than 10,000 deaths from AML.5 The five-year survival rate of AML reported from 2007 to 2013 was approximately 27 percent, which was the lowest of all leukemias.4

FLT3 gene mutations are one of the most common genetic abnormalities in AML.6 FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML.7,8,9,10 FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML.8,11 Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.12,13

MDS is a type of cancer that can occur when blood-forming cells in the bone marrow become abnormal.14 There were over 14,000 new cases of MDS diagnosed each year from 2010 to 2014.4 In about one in three patients, MDS progresses to AML.14

About Quizartinib

Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective type II FLT3 inhibitor currently in phase 3 development for relapsed/refractory FLT3-ITD AML (QuANTUM-R) in the U.S. and EU; phase 3 development for newly-diagnosed FLT3-ITD AML (QuANTUM-First) in the U.S., EU and Japan; phase 2 development for relapsed/refractory FLT3-ITD AML in Japan; and phase 1 development in combination with an investigational agent, milademetan, for relapsed/refractory FLT3-ITD AML and newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S., EU and Japan.

Quizartinib has been granted Priority Review and Breakthrough Therapy designation for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, and Fast Track designation for the treatment of relapsed/refractory AML by the U.S. Food and Drug Administration (FDA). Quizartinib also has been granted accelerated assessment by the European Medicines Agency (EMA) for the treatment of adults with relapsed or refractory AML, which is FLT3-ITD positive, and granted Orphan Drug designation by both the FDA and the European Commission (EC) for the treatment of AML and by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of FLT3-mutated AML.

About Milademetan

Milademetan (DS-3032) is an oral selective MDM2 inhibitor currently in phase 1 clinical development for solid and hematologic malignancies, including a combination study with quizartinib in relapsed/refractory FLT3-ITD AML or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S., EU and Japan; a single agent and combination study with 5-azacitidine in newly-diagnosed AML unfit for intensive chemotherapy, relapsed/refractory AML or high-risk MDS in the U.S.; and two single agent studies in lymphomas and solid tumors in the U.S. and Japan.

Quizartinib and milademetan are investigational agents that have not been approved for any indication in any country. Safety and efficacy of these investigational agents have not been established.